In general, the present invention relates to small molecule heterocyclic inhibitors of sepiapterin reductase (SPR), and to the medical use of these compounds.
Tetrahydrobiopterin (BH4), which has the following structure,
is an essential cofactor of hydroxylase enzymes that are involved in the synthesis of neurotransmitters such as serotonin, melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and nitric oxide (NO). SPR catalyzes the final step in the BH4 synthetic pathway, which is the conversion of 6-pyruvoyl tetrahydropterin to BH4. SPR is also one of the two enzymes involved in de novo BH4 synthesis that is up-regulated in preclinical pain models, and reducing the activity of these enzymes leads to preclinical pain relief (Tegeder et al., Nature Medicine 12:1269-1277, 2006). Accordingly, the inhibition of SPR can be a useful target for developing new methods for the treatment or prevention of pain.